Novel tetrahydro-1h-pyrido[4,3-b]indoles

ABSTRACT

This invention relates to novel tetrahydro-1H-pyrido[4,3-b]indoles, their derivatives and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by NMDA antagonists, acetylcholinesterase inhibitors, 5-HT6 antagonists, other neuroprotectors, antihistamines and agents that delay age-related pathologies and conditions.

RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 61/200,206,filed Nov. 25, 2008. The entire teachings of the above applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

Dimebolin, also known as dimebon and2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoledihydrochloride, has a wide array of biological activities includingantihistamine properties, NMDA antagonism, delay of age-relatedpathologies and conditions, and neuroprotection modulates.

Dimebolin is currently in Phase II trials for Huntington's disease andPhase III trials for Alzheimer's-type dementia. Dimebolin has been usedto treat allergic rhinitis and skin allergies in Russia for the past 25years.

Despite the beneficial activities of dimebolin, there is a continuingneed for new compounds to treat the aforementioned diseases andconditions.

SUMMARY OF THE INVENTION

This invention relates to novel tetrahydro-1H-pyrido[4,3-b]indoles,their derivatives and pharmaceutically acceptable salts thereof. Thisinvention also provides compositions comprising a compound of thisinvention and the use of such compositions in methods of treatingdiseases and conditions that are beneficially treated by NMDAantagonists, acetylcholinesterase inhibitors, 5-HT6 antagonists, otherneuroprotectors, antihistamines and agents that delay age-relatedpathologies and conditions.

DETAILED DESCRIPTION OF THE INVENTION

The terms “ameliorate” and “treat” are used interchangeably and includeboth therapeutic and prophylactic treatment. Both terms mean decrease,suppress, attenuate, diminish, arrest, or stabilize the development orprogression of a disease (e.g., a disease or disorder delineatedherein), lessen the severity of the disease or improve the symptomsassociated with the disease.

“Disease” means any condition or disorder that damages or interfereswith the normal function of a cell, tissue, or organ.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of dimebolin willinherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes,notwithstanding this variation, is small and immaterial as compared tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada E et al., Seikagaku 1994, 66:15;Ganes L Z et al., Comp Biochem Physiol Mol Integr Physiol 1998, 119:725.

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Also unlessotherwise stated, when a position is designated specifically as “D” or“deuterium”, the position is understood to have deuterium at anabundance that is at least 3340 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., at least 50.1% incorporation ofdeuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

The term “isotopologue” refers to a species that differs from a specificcompound of this invention only in the isotopic composition thereof.

The term “compound,” when referring to a compound of this invention,refers to a collection of molecules having an identical chemicalstructure, except that there may be isotopic variation among theconstituent atoms of the molecules. Thus, it will be clear to those ofskill in the art that a compound represented by a particular chemicalstructure containing indicated deuterium atoms, will also contain lesseramounts of isotopologues having hydrogen atoms at one or more of thedesignated deuterium positions in that structure. The relative amount ofsuch isotopologues in a compound of this invention will depend upon anumber of factors including the isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthesis steps used to prepare the compound.However, as set forth above the relative amount of such isotopologues intoto will be less than 49.9% of the compound. In other embodiments, therelative amount of such isotopologues in toto will be less than 47.5%,less than 40%, less than 32.5%, less than 25%, less than 17.5%, lessthan 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% ofthe compound.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephathalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

The compounds of the present invention (e.g., compounds of Formula I),may contain an asymmetric carbon atom, for example, as the result ofdeuterium substitution or otherwise. As such, compounds of thisinvention can exist as either individual enantiomers, or mixtures of thetwo enantiomers. Accordingly, a compound of the present invention mayexist as either a racemic mixture or a scalemic mixture, or asindividual respective stereoisomers that are substantially free fromanother possible stereoisomer. The term “substantially free of otherstereoisomers” as used herein means less than 25% of otherstereoisomers, preferably less than 10% of other stereoisomers, morepreferably less than 5% of other stereoisomers and most preferably lessthan 2% of other stereoisomers, or less than “X”% of other stereoisomers(wherein X is a number between 0 and 100, inclusive) are present.Methods of obtaining or synthesizing an individual enantiomer for agiven compound are known in the art and may be applied as practicable tofinal compounds or to starting material or intermediates.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The term “stable compounds,” as used herein, refers to compounds whichpossess stability sufficient to allow for their manufacture and whichmaintain the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediate compounds, treating adisease or condition responsive to therapeutic agents).

“D” and “d” both refer to deuterium. “Stereoisomer” refers to bothenantiomers and diastereomers. “Tert”, ^(“t”), and “t-” each refer totertiary. “US” refers to the United States of America.

Throughout this specification, a variable may be referred to generally(e.g., “each R”) or may be referred to specifically (e.g., R¹, R², R³,etc.). Unless otherwise indicated, when a variable is referred togenerally, it is meant to include all specific embodiments of thatparticular variable.

Therapeutic Compounds

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

each R is independently selected from CH₃, CD₂H, CDH₂ and CD₃;

each X is independently selected from H and D;

each Y is independently selected from H and D;

each Z is independently selected from H and D; and

when each R is CH₃, at least one X, Y or Z is D.

In one embodiment, each X¹ is the same; each X² is the same; each X³ isthe same; each Y is the same; and each Z is the same.

In another embodiment, each X¹, X², and X³ is hydrogen.

In another embodiment, each X¹, X², and X³ is deuterium.

In another embodiment, each R is independently selected from CH₃ andCD₃. In one aspect of this embodiment, each X is D; each Y is the same;and each Z is the same.

Specific examples of compounds of Formula I where each X is D are shownin Table 1 below.

TABLE 1 Exemplary Embodiments of Formula I Compound R¹ R² R³ each Y eachZ 100 CD₃ CD₃ CD₃ D D 101 CD₃ CD₃ CD₃ D H 102 CD₃ CD₃ CD₃ H D 103 CD₃CD₃ CH₃ D D 104 CD₃ CD₃ CH₃ D H 105 CD₃ CD₃ CH₃ H D 106 CD₃ CH₃ CD₃ D D107 CD₃ CH₃ CD₃ D H 108 CD₃ CH₃ CD₃ H D 109 CH₃ CD₃ CD₃ D D 110 CH₃ CD₃CD₃ D H 111 CH₃ CD₃ CD₃ H D 112 CH₃ CH₃ CD₃ D D 113 CH₃ CH₃ CD₃ D H 114CH₃ CH₃ CD₃ H D 115 CH₃ CD₃ CH₃ D D 116 CH₃ CD₃ CH₃ D H 117 CH₃ CD₃ CH₃H D 118 CD₃ CH₃ CH₃ D D 119 CD₃ CH₃ CH₃ D H 120 CD₃ CH₃ CH₃ H D 121 CH₃CH₃ CH₃ D D 122 CH₃ CH₃ CH₃ D H 123 CH₃ CH₃ CH₃ H D 124 CD₃ CD₃ CD₃ H H125 CD₃ CH₃ CD₃ H H 126 CD₃ CD₃ CH₃ H H 127 CH₃ CD₃ CD₃ H H 128 CH₃ CH₃CD₃ H H 129 CH₃ CD₃ CH₃ H H 130 CD₃ CH₃ CH₃ H H 131 CH₃ CH₃ CH₃ H H

In another set of embodiments, any atom not designated as deuterium inany of the embodiments set forth above is present at its naturalisotopic abundance.

The synthesis of compounds of Formula I can be readily achieved bysynthetic chemists of ordinary skill. Relevant procedures andintermediates are disclosed, for instance in patent publication SU1138164 A1, Vinogradova, E V et al, Zhurnal Obshchei Khimii 1962,32:1550, U.S. Pat. No. 3,409,628 and PCT publication WO 2008060190.

Such methods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure.

Exemplary Synthesis

Methods for synthesizing compounds of Formula I are depicted in Scheme 1and subsequent schemes.

According to Scheme 1, a compound of Formula I can be prepared bytreating an appropriately deuterated p-tolyl-hydrazine 10 with anappropriately deuterated piperidin-4-one 11 in the presence deuteratedsulfuric acid according to the procedure described by Vinogradova, E Vet al, Zhurnal Obshchei Khimii 1962, 32: 1550-1556 provides a compoundof formula I.

Scheme 2 depicts the synthesis of deuterated p-tolyl-hydrazine 10. Thus,treatment of an appropriately deuterated aniline 20 with anappropriately deuterated 3-pyridyl-acetic acid 21 in the presence ofN-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide) (“EDC”),1-hydroxybenzotriazole hydrate (“HOBt”), and N-methylmorpholine (“NMM”)according to the procedure described in Korosec, T et al, Biorg Med Chem2008, 16: 209-221 gives the deuterated amide 22. Subsequent reduction ofthe amide 22 using deuterated borane or borane, again according toprotocol of Korosec, T et al, supra, affords the appropriatelydeuterated (1-p-tolylhydrazinyl)ethylpyridine 23. Treatment of thatintermediate 23 with sodium nitrite in the presence of deuteriumchloride in D₂O according to the procedure described by Vinogradova, E Vet al, Zhurnal Obshchei Khimii 1962, 32: 1550-1556 affords theN-nitroso-amine 24. Reduction of the N-nitroso-amine 24 is accomplishedby treatment with zinc in the presence of d₁-acetic acid and D₂Oaccording to the procedure described by in U.S. Pat. No. 3,409,628 toafford the desired deuterated p-tolyl-hydrazine derivative 10.

Specific anilines of 20 which is useful in Scheme 2 is commerciallyavailable.

Scheme 3 depicts the synthesis of a deuterated 3-pyridyl-acetic acid of21. Thus, treatment of commercially available 6-methyl-3-pyridineaceticacid 50 with sodium deuteroxide in D₂O at 100° C. according to theprocedure described by Foote, C S et al, J Am Chem Soc 1990, 112:3607-3614 affords the desired2,2-dideutero-2-(6-(trideuteromethyl)pyridin-3-yl)acetic acid 21.

Scheme 4 depicts the synthesis of deuterated piperidin-4-one 11. Thus,treatment of commercially available methyl acrylate-d6 30 with anappropriately deuterated primary amine 31 according to the proceduredescribed in Chinese patent publication CN 1590387A gives theappropriately deuterated amino-diester 32. Dieckmann cyclization of theamino ester 32 is accomplished by treatment with sodium deuteromethoxidein MeOD using the protocol in CN 1590387A to give the appropriatelydeuterated β-keto-ester 33. Finally, saponification and decarboxylationof the β-keto-ester 33 with sodium deuteroxide in D₂O according to theprocedures in CN 1590387A affords an appropriately deuteratedpiperidin-4-one 11.

The specific approaches and compounds shown above are not intended to belimiting. The chemical structures in the schemes herein depict variablesthat are hereby defined commensurately with chemical group definitions(moieties, atoms, etc.) of the corresponding position in the compoundformulae herein, whether identified by the same variable name (i.e., R¹,R², R³, etc.) or not. The suitability of a chemical group in a compoundstructure for use in the synthesis of another compound is within theknowledge of one of ordinary skill in the art.

Additional methods of synthesizing compounds of Formula I and theirsynthetic precursors, including those within routes not explicitly shownin schemes herein, are within the means of chemists of ordinary skill inthe art. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing theapplicable compounds are known in the art and include, for example,those described in Larock R, Comprehensive Organic Transformations, VCHPublishers (1989); Greene T W et al., Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley and Sons (1999); Fieser L et al.,Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons(1994); and Paquette L, ed., Encyclopedia of Reagents for OrganicSynthesis, John Wiley and Sons (1995) and subsequent editions thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

Compositions

The invention also provides pyrogen-free pharmaceutical compositionscomprising an effective amount of a compound of Formula I (e.g.,including any of the formulae herein), or a pharmaceutically acceptablesalt of said compound; and a pharmaceutically acceptable carrier. Thecarrier(s) are “acceptable” in the sense of being compatible with theother ingredients of the formulation and, in the case of apharmaceutically acceptable carrier, not deleterious to the recipientthereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds of thepresent invention in pharmaceutical compositions may be enhanced bymethods well-known in the art. One method includes the use of lipidexcipients in the formulation. See “Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs andthe Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare,2007; and “Role of Lipid Excipients in Modifying Oral and ParenteralDrug Delivery: Basic Principles and Biological Examples,” Kishor M.Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this invention optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866; and United States patent publications 20060094744 and20060079502.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets, sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington's Pharmaceutical Sciences, Mack Publishing Company,Philadelphia, Pa. (17th ed. 1985).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In certain embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thepatient, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of this invention further comprisesa second therapeutic agent. The second therapeutic agent may be selectedfrom any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with a compoundhaving the same mechanism of action as dimebolin. Such agents includethose indicated as being useful in combination with dimebolin, includingbut not limited to, those described in PCT publications WO1997015225,WO2007041697, WO2007087425, WO2008036410, WO2008051599, WO2008069963 andWO2008073231.

Preferably, the second therapeutic agent is an agent useful in thetreatment or prevention of a disease or condition selected from chronicpain, neuropathic pain, cerebrovascular disorders, Alzheimer's disease,Huntington's disease, ALS, cognitive disorders, and dementia.

According to one embodiment, the second therapeutic agent is selectedfrom an acetylcholinesterase inhibitor, a butyrylcholinesteraseinhibitor, an acetylcholine receptor agonist, a NMDA receptorantagonist, an inhibitor of amyloid A peptide or amyloid plaque, aphosphodiesterase 5 (PDE5) inhibitor, a phosphodiesterase 4 (PDE4)inhibitor, a monoamine oxidase inhibitor, a VEGF protein, a trophicgrowth factor, a HIF activator, a HIF prolyl 4-hydroxylases inhibitor,an anti-apoptotic compound, an ADNP agonist or analog, an ADNF agonistor analog, an activator of an AMPA-type glutamate receptor, a serotonin5-HTIA receptor agonist, a serotonin IA receptor antagonist, a nicotinicalpha-7 receptor agonist, a neuronal L-type calcium channel modulator, a5-HT4 receptor agonist, and an anti-inflammatory agent.

In another embodiment, the second therapeutic agent is selected fromdonepezil, rivastigmine, galantamine, memantine, or a pharmaceuticallyacceptable salt of any of the foregoing.

In yet another embodiment, the second therapeutic agent is donepezilhydrocholoride.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to treat (therapeutically orprophylactically) the target disorder. For example, to reduce orameliorate the severity, duration or progression of the disorder beingtreated, prevent the advancement of the disorder being treated, causethe regression of the disorder being treated, or enhance or improve theprophylactic or therapeutic effect(s) of another therapy.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from 1 mg to 500 mg per day. In another embodiment, aneffective amount of a compound of this invention can range from 10 mg to100 mg per day. In another embodiment, an effective amount of a compoundof this invention can range from 20 mg to 60 mg per day. A daily amountcan be administered in from 1 to 3 separate doses per day.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe patient, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the amounts used safely inclinical trials and/or prescribing information for dimebolin.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of this invention.When this occurs, it will allow the effective dosage of the secondtherapeutic agent and/or the compound of this invention to be reducedfrom that required in a monotherapy. This has the advantage ofminimizing toxic side effects of either the second therapeutic agent ofa compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

According to one embodiment, the invention provides a method of treatinga disease that is beneficially treated by dimebolin in a patient in needthereof, comprising the step of administering to the patient aneffective amount of a compound or a composition of this invention. Suchdiseases are well known in the art and include, but are not limited to,chronic pain, neuropathic pain, cerebrovascular disorders, cognitivedisorders, dementia, Alzheimer's disease, Huntington's disease and ALS.

In one particular embodiment, the method of this invention is used totreat a disease or condition selected from Alzheimer's disease andHuntington's disease in a patient in need thereof

Identifying a patient in need of such treatment can be in the judgmentof a patient or a health care professional and can be subjective (e.g.opinion) or objective (e.g. measurable by a test or diagnostic method).

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to the patient in need thereof oneor more second therapeutic agents. The choice of second therapeuticagent may be made from any second therapeutic agent known to be usefulfor co-administration with Compound 1. The choice of second therapeuticagent is also dependent upon the particular disease or condition to betreated. Examples of second therapeutic agents that may be employed inthe methods of this invention are those set forth above for use incombination compositions comprising a compound of this invention and asecond therapeutic agent.

In particular, the invention provides a method of treating Alzheimer'sdisease in a patient in need thereof comprising the step ofco-administering to the patient a pharmaceutically acceptablecomposition comprising a compound of Formula I and a second therapeuticagent selected from donepezil, rivastigmine, galantamine, memantine, ora pharmaceutically acceptable salt of any of the foregoing. In oneparticular aspect, the second therapeutic agent is donepezilhydrochloride.

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of theinvention and a second therapeutic agent, to a patient does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidpatient at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of a compound ofFormula I alone or together with one or more of the above-describedsecond therapeutic agents in the manufacture of a medicament, either asa single composition or as separate dosage forms, for treatment orprevention in a patient of a disease, disorder or symptom set forthabove. Another aspect of the invention is a compound of Formula I foruse in the treatment or prevention in a patient of a disease, disorderor symptom thereof delineated herein.

Pharmaceutical Kits

The present invention also provides kits for use to treat Alzheimer'sdisease or Huntington's disease. These kits comprise (a) apharmaceutical composition comprising a compound of Formula I or apharmaceutically acceptable salt thereof, wherein said pharmaceuticalcomposition is in a container; and (b) instructions describing a methodof using the pharmaceutical composition to treat Alzheimer's disease orHuntington's disease.

The container may be any vessel or other sealed or sealable apparatusthat can hold said pharmaceutical composition. Examples include bottles,ampules, divided or multi-chambered holders bottles, wherein eachdivision or chamber comprises a single dose of said composition, adivided foil packet wherein each division comprises a single dose ofsaid composition, or a dispenser that dispenses single doses of saidcomposition. The container can be in any conventional shape or form asknown in the art which is made of a pharmaceutically acceptablematerial, for example a paper or cardboard box, a glass or plasticbottle or jar, a re-sealable bag (for example, to hold a “refill” oftablets for placement into a different container), or a blister packwith individual doses for pressing out of the pack according to atherapeutic schedule. The container employed can depend on the exactdosage form involved, for example a conventional cardboard box would notgenerally be used to hold a liquid suspension. It is feasible that morethan one container can be used together in a single package to market asingle dosage form. For example, tablets may be contained in a bottle,which is in turn contained within a box. In one embodiment, thecontainer is a blister pack.

The kits of this invention may also comprise a device to administer orto measure out a unit dose of the pharmaceutical composition. Suchdevice may include an inhaler if said composition is an inhalablecomposition; a syringe and needle if said composition is an injectablecomposition; a syringe, spoon, pump, or a vessel with or without volumemarkings if said composition is an oral liquid composition; or any othermeasuring or delivery device appropriate to the dosage formulation ofthe composition present in the kit.

In certain embodiment, the kits of this invention may comprise in aseparate vessel of container a pharmaceutical composition comprising asecond therapeutic agent, such as one of those listed above for use forco-administration with a compound of this invention.

Evaluation of Metabolic Stability

Certain in vitro liver metabolism studies have been described previouslyin the following references, each of which is incorporated herein intheir entirety: Obach, R S, Drug Metab Disp, 1999, 27:1350; Houston, J Bet al., Drug Metab Rev, 1997, 29:891; Houston, J B, Biochem Pharmacol,1994, 47:1469; Iwatsubo, T et al., Pharmacol Ther, 1997, 73:147; andLave, T, et al., Pharm Res, 1997, 14:152.

Microsomal Assay: Human liver microsomes (20 mg/mL) are obtained fromXenotech, LLC (Lenexa, Kans.). β-nicotinamide adenine dinucleotidephosphate, reduced form (NADPH), magnesium chloride (MgCl₂), anddimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich. Theincubation mixtures are prepared according to Table 2:

TABLE 2 Reaction Mixture Composition for Human Liver Microsome StudyLiver Microsomes 3.0 mg/mL Potassium Phosphate, pH 7.4 100 mM MagnesiumChloride 10 mM

Determination of Metabolic Stability: Two aliquots of this reactionmixture are used for a compound of this invention. The aliquots areincubated in a shaking water bath at 37° C. for 3 minutes. The testcompound is then added into each aliquot at a final concentration of 0.5μM. The reaction is initiated by the addition of cofactor (NADPH) intoone aliquot (the other aliquot lacking NADPH serves as the negativecontrol). Both aliquots are then incubated in a shaking water bath at37° C. Fifty microliters (50 μL) of the incubation mixtures arewithdrawn in triplicate from each aliquot at 0, 5, 10, 20, and 30minutes and combined with 50 μL of ice-cold acetonitrile to terminatethe reaction. The same procedure is followed for Compound 1 and thepositive control. Testing is done in triplicate.

Data analysis: The in vitro half-lives (t_(1/2)s) for test compounds arecalculated from the slopes of the linear regression of % parentremaining (ln) vs incubation time relationship.

in vitro t_(1/2)=0.693/k

k=−[slope of linear regression of % parent remaining (ln) vs incubationtime]

Data analysis is performed using Microsoft Excel Software.

The metabolic stability of compounds of Formula I is tested using pooledliver microsomal incubations. Full scan LC-MS analysis is then performedto detect major metabolites. Samples of the test compounds, exposed topooled human liver microsomes, are analyzed using HPLC-MS (or MS/MS)detection. For determining metabolic stability, multiple reactionmonitoring (MRM) is used to measure the disappearance of the testcompounds. For metabolite detection, Q1 full scans are used as surveyscans to detect the major metabolites.

SUPERSOMES™ Assay. Various human cytochrome P450-specific SUPERSOMES™are purchased from Gentest (Woburn, Mass., USA). A 1.0 mL reactionmixture containing 25 pmole of SUPERSOMES™, 2.0 mM NADPH, 3.0 mM MgCl,and 1 μM of a compound of Formula I in 100 mM potassium phosphate buffer(pH 7.4) is incubated at 37° C. in triplicate. Positive controls contain1 μM of dimebolin instead of a compound of formula I. Negative controlsused Control Insect Cell Cytosol (insect cell microsomes that lacked anyhuman metabolic enzyme) purchased from GenTest (Woburn, Mass., USA).Aliquots (50 μL) are removed from each sample and placed in wells of amulti-well plate at various time points (e.g., 0, 2, 5, 7, 12, 20, and30 minutes) and to each aliquot is added 50 μL of ice cold acetonitrilewith 3 μM haloperidol as an internal standard to stop the reaction.

Plates containing the removed aliquots are placed in −20° C. freezer for15 minutes to cool. After cooling, 100 μL of deionized water is added toall wells in the plate. Plates are then spun in the centrifuge for 10minutes at 3000 rpm. A portion of the supernatant (100 μL) is thenremoved, placed in a new plate and analyzed using Mass Spectrometry.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention. All the patents,journal articles and other documents discussed or cited above are hereinincorporated by reference.

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: each R isindependently selected from CH₃, CD₂H, CDH₂ and CD₃; each X isindependently selected from H and D; each Y is independently selectedfrom H and D; each Z is independently selected from H and D; and wheneach R is CH₃, at least one X, Y or Z is D.
 2. The compound of claim 1,wherein: each X¹ is the same; each X² is the same; each X³ is the same;each Y is the same; each Z is the same.
 3. The compound of claim 1,wherein each X¹, X², and X³ is deuterium.
 4. The compound of claim 1,wherein each R is independently selected from CH₃ and CD₃.
 5. Thecompound of claim 4, wherein each X is the same.
 6. The compound ofclaim 5, wherein each X is D.
 7. The compound of claim 6, wherein thecompound is selected from one of the compounds set forth in the tablebelow: Compound R¹ R² R³ each Y each Z 100 CD₃ CD₃ CD₃ D D 101 CD₃ CD₃CD₃ D H 102 CD₃ CD₃ CD₃ H D 103 CD₃ CD₃ CH₃ D D 104 CD₃ CD₃ CH₃ D H 105CD₃ CD₃ CH₃ H D 106 CD₃ CH₃ CD₃ D D 107 CD₃ CH₃ CD₃ D H 108 CD₃ CH₃ CD₃H D 109 CH₃ CD₃ CD₃ D D 110 CH₃ CD₃ CD₃ D H 111 CH₃ CD₃ CD₃ H D 112 CH₃CH₃ CD₃ D D 113 CH₃ CH₃ CD₃ D H 114 CH₃ CH₃ CD₃ H D 115 CH₃ CD₃ CH₃ D D116 CH₃ CD₃ CH₃ D H 117 CH₃ CD₃ CH₃ H D 118 CD₃ CH₃ CH₃ D D 119 CD₃ CH₃CH₃ D H 120 CD₃ CH₃ CH₃ H D 121 CH₃ CH₃ CH₃ D D 122 CH₃ CH₃ CH₃ D H 123CH₃ CH₃ CH₃ H D 124 CD₃ CD₃ CD₃ H H 125 CD₃ CH₃ CD₃ H H 126 CD₃ CD₃ CH₃H H 127 CH₃ CD₃ CD₃ H H 128 CH₃ CH₃ CD₃ H H 129 CH₃ CD₃ CH₃ H H 130 CD₃CH₃ CH₃ H H 131 CH₃ CH₃ CH₃ H H

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, wherein any atom not designated as deuterium is present at itsnatural abundance.
 9. A pyrogen-free pharmaceutical compositioncomprising a compound of claim 1; and a pharmaceutically acceptablecarrier.
 10. The composition of claim 9, further comprising a secondtherapeutic agent useful in the treatment of a disease or conditionselected from chronic pain, neuropathic pain, cerebrovascular disorders,Alzheimer's disease, Huntington's disease, ALS, cognitive disorders, anddementia.
 11. The composition of claim 10, wherein the secondtherapeutic agent is selected from an acetylcholinesterase inhibitor, abutyrylcholinesterase inhibitor, an acetylcholine receptor agonist, aNMDA receptor antagonist, an inhibitor of amyloid A peptide or amyloidplaque, a phosphodiesterase 5 (PDE5) inhibitor, a phosphodiesterase 4(PDE4) inhibitor, a monoamine oxidase inhibitor, a VEGF protein, atrophic growth factor, a HIF activator, a HIF prolyl 4-hydroxylasesinhibitor, an anti-apoptotic compound, an ADNP agonist or analog, anADNF agonist or analog, an activator of an AMPA-type glutamate receptor,a serotonin 5-HTIA receptor agonist, a serotonin IA receptor antagonist,a nicotinic alpha-7 receptor agonist, a neuronal L-type calcium channelmodulator, a 5-HT4 receptor agonist, and an anti-inflammatory agent. 12.The composition of claim 11, wherein the second therapeutic is selectedfrom donepezil, rivastigmine, galantamine, memantine, or apharmaceutically acceptable salt of any of the foregoing.
 13. A methodof treating a disease or condition selected from chronic pain,neuropathic pain, cerebrovascular disorders, cognitive disorders,dementia, Alzheimer's disease, Huntington's disease and ALS in a patientin need thereof, the method comprising the step of administering to thepatient an effective amount of a composition of claim
 9. 14. The methodof claim 13, wherein the disease is selected from Alzheimer's diseaseand Huntington's disease.
 15. The method of claim 13 comprising theadditional step of co-administering to the patient in need thereof asecond therapeutic agent selected from an acetylcholinesteraseinhibitor, a butyrylcholinesterase inhibitor, an acetylcholine receptoragonist, a NMDA receptor antagonist, an inhibitor of amyloid A peptideor amyloid plaque, a phosphodiesterase 5 (PDE5) inhibitor, aphosphodiesterase 4 (PDE4) inhibitor, a monoamine oxidase inhibitor, aVEGF protein, a trophic growth factor, a HIF activator, a HIF prolyl4-hydroxylases inhibitor, an anti-apoptotic compound, an ADNP agonist oranalog, an ADNF agonist or analog, an activator of an AMPA-typeglutamate receptor, a serotonin 5-HTIA receptor agonist, a serotonin IAreceptor antagonist, a nicotinic alpha-7 receptor agonist, a neuronalL-type calcium channel modulator, a 5-HT4 receptor agonist, and ananti-inflammatory agent.
 16. The method of claim 15, wherein the secondtherapeutic is selected from donepezil, rivastigmine, galantamine,memantine, or a pharmaceutically acceptable salt of any of theforegoing.
 17. The method of claim 16, wherein the disease isAlzheimer's disease and the second therapeutic agent is donepezilhydrochloride.